Fertility Preservation for Breast Cancer Elizabeth S. Ginsburg MD Medical Director, ART Program Brigham & Women s Hospital
Learning Objectives To be able to list and describe processes of ovulation induction and oocyte cryopreservation To be able to counsel patients about the meaning of serum AMH level To be able to discuss the evidence surrounding ovarian suppression during chemotherapy
Disclosures Royalties Up to Date, Biomed Central Investigator initiated study, Serono financial support Advance medical consultant
American Society of Clinical Oncology Guidelines As part of informed consent process reproductive age men and women with cancer should have potential impact of cancer and its treatment discussed Fertility preservation options should be presented and referral to fertility specialist should be offered Lee SJ, et al. American Society of Clinical Oncology Recommendations On Fertility Preservation in Cancer Patients. J Clin Oncol 2006 Loren AW, et al. Fertility Preservation for Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2013 Breast cancer survivors who discuss fertility preservation have better well being Letourneau JM, et al. Pretreatment Fertility Counseling and Fertility Preservation Improve Quality of Life in Reproductive Age Women with Cancer. Caner, 2012
Assisted Reproduction Outcomes in Female Cancer Survivors Female cancer survivors undergoing IVF/ICSI at BWH from 1998 2009. IVF outcomes compared to other infertility patients in 2 comparison groups. Pregnancy and live birth rates significantly lower Risk of cancelation of egg retrieval due to poor response significantly higher Barton SE, et al. Female Cancer Survivors are Low Responders and have Reduced Success compared with Other Patients Undergoing Assisted Reproductive Technologies. Fertil Steril, 2012.
Breast Cancer Treatment Chemotherapy (cyclophosphamide, adriamycin + taxotere + herceptin) Various administration regimens Tamoxifen: 10 year delay prior to conception attempts if completed Increasing maternal age 30 57% of young women who try to conceive after breast cancer are successful Ives A, et al. Pregnancy after Breast Cancer: Population Based Study. BMJ, 2007. Dalberg K, et al. Birth Outcome in Women with Previously Treated Breast Cancer A Population Based Cohort Study from Sweden. PLOS Med, 2006
Impact of Chemotherapy on Ovarian Reserve Alkylating agents particularly accelerate follicular depletion Mechanisms: Mediated by sphingomyelinase gene produces ceramide which stimulates apoptosis Blocking sphingomyelinase gene prevents chemotherapy induced follicular apoptosis Zelinski MB, et al. In Vivo Delivery of FTY720 Prevents Radiation Induced Ovarian Failure and Infertility in Adult Female Nonhuman Primates. Fertil Steril, 2011
Fertility Preservation Options Oocyte (egg) freezing Embryo freezing Ovarian suppression Ovarian tissue cryopreservation (experimental) Research on ovarian protecting agents
Ovarian Reserve Testing Normal AMH > 0.9 ng/ml Antral follicle count Number of follicles 2 9 mm in both ovaries: normal > 6 Both are predictive of egg and embryo number, not quality Dose gonadotropins higher if AMH < 1.2, AFC < 6 AMH poorly predictive of pregnancy in young women Can be abnormal in fertile women Dolleman M, et al. The Relationship Between Anti Nullerian Hormone in Women Receiving Fertility Assessments and Age at Meopause in Subfertile Women: Evidence From Large Population Studies. J Clin Endocrinol Metab, 2013 Complex factors including AMH, age and chemotherapy agents predict post treatment menses Barnabei A, et al. Predicting Ovarian Activity in Women Affected by Early Breast Cancer: A Meta Analysis Based Nomogram. Oncologist, 2015
AMH Over Lifetime Fong SL, et al. Serum Anti Mullerrian Hormone Levels in Healthy Females: A Nomogram Ranging from Infancy to Addulthood. J Clin Endocrinol Metab, 2012
Ovarian Function During the Recovery Period- after Chemo (mean + SEM) Dynamics and mechanisms of chemotherapy induced ovarian follicular depletion in women of fertile age Rosendahl M, et al. Dynamics and Mechanisms of Chemotherapy Induced Ovarian Follicular Depletion in Women of Fertile Age. Fertil Steril, 2010.
Oocyte / Embryo Cryopreservation
Ovulation Induction Goal: obtain good number of eggs/ embryos in women who will be unable to conceive without them 15 eggs optimizes pregnancy rates in non cancer scenario Some recommend low FSH dosing, but egg number will be lower Lee S, et al. Does Higher Starting Dose of FSH Stimulation with Letrozole Improve Fertility Preservation Outcomes in Women with Breast Cancer? Fertil Steril, 2012
Dilemma Whenever possible, perform fertility preservation procedures before chemotherapy Not always possible with neoadjuvant chemotherapy Mouse data suggest that IVF performed soon after cyclophosphamide chemotherapy may result in chromosomally abnormal offspring. Barekati Z, et al. Previous Maternal Chemotherapy by Cyclophosphamide (Cp) Causes Numerical Chromosome Abnormalities in Preimplantation Mouse Embryos. Reprod Toxicol 2008
Estrogen Receptor Positive Cancers Letrozole daily during stimulation 2.5 or 5.0mg if ER+ Usually maintains physiologic estradiol levels Unclear if elevated estradiol levels are harmful Unclear if any impact of letrozole has on egg quality Given utility in PCO, probably not harmful
Stimulation for estrogen sensitive tumors: letrozole 1. Start letrozole on cycle day 2 3 or random 2. Start gonadotropins 3. Add GnRH antagonist when lead follicle reaches 14 mm. 4. Trigger when lead follicles reach 19 21 mm 36 h prior to retrieval 5. Some check estradiol 3 days after retrieval. If >250 pg/ml restart letrozole. Start Trigger Antagonist Oocyte Retrieval Gonadotropins Letrozole +/- Letrozole Random Start or Cycle Day 2 Cycle Day Oktay K, et al. Letrozole Redues Estrogen and Gonadotropin Exposure in Women with Breast Cancer Undergoing Ovarian Stimulation before Chemotherapy. J Clin Endocrinol Metab, 2006.
Oocyte Retrieval Retrieval: Transabdominal Approach (Oophoropexy/ Obesity) Barton SE, et al. Female Cancer Survivors are Low Responders and have Reduced Success compared with Other Patients Undergoing Assisted Reproductive Technologies. Fertil Steril, 2012.
Short Stimulation/ Natural Cycle (not recommended) Can give hcg without stimulation or only 2 3 days of stimulation, retrieve immature oocytes, in vitro mature, and then freeze Must use 19 G needle and curette follicles extensively Much lower numbers of oocytes (1 5) Maman E, et al. Luteal Phase Oocyte Retrieval and In Vitro Maturation is an Optional Procedure for Urgent Fertility Preservation. Fertil Steril, 2011 If patient is stable and fertility is important waiting additional week to start chemotherapy is reasonable to get higher numbers of eggs/ embryos
Ovarian Response in Breast Cancer Patients Molly MQ, et al. Response to Ovarian Stimulation is not Impacted by a Breast Cancer Diagnosis. Hum Reprod, 2017
Ovulation Induction in BRCA+ & BRCA- Patients All results reported as mean ± standard deviation, unless otherwise noted. * indicates statistical significance (p value <0.05) Poisson regression estimate, RR (95% CI), Adjusted for age and BMI at cycle start Linear regression estimate, β (95% CI), Adjusted for age and BMI at cycle start Poisson regression estimate, β (95% CI), Adjusted for age and BMI at cycle start, and ICSI use Logistic regression estimate, OR (95% CI), Adjusted for age and BMI at cycle start Dolinko A and Ginsburg ES, et al. New Data 2016.
Safety of Controlled Ovarian Stimulation in Estrogen Sensitive Tumors Compared 79 breast cancer patients (81% ER positive) undergoing letrozole stimulation with 136 controls who did not undergo ovarian stimulation No difference in relapse free survival over study follow up period (median 2 years) Non randomized study and longterm follow up not yet available Azim AA, et al. Safety of Fertility Preservation by Ovarian Stimulation With Letrozole and Gonadotropins in Patients with Breast Cander: a Prospective controlled Study. J Clin Oncol, 2008
Embryo/ Oocyte Cryopreservation We vitrify embryos at 2 PN stage >90% survival No concern about loss of embryos from poor cleavage or blastocyst development Will find out about embryo development in future We typically thaw 2 4 depending on age at cryopreservation Oocyte cryopreservation Vitrification provides >90% survival Most deliveries from MII oocytes We freeze all oocytes In vitro maturation likely to improve
Using Oocytes/Embryos after Cancer Assess health of survivor Cancer therapies may have significant toxicities Maternal fetal medicine (MFM) consultation recommended Cardio pulmonary assessment Uterine evaluation Gestational surrogacy may be an option Sexually transmitted disease screening tests Legal consultation Very costly Preimplantation genetic diagnosis (PGD) an option for genetic cancers Need a large number of embryos
Embryo Cryo Outcome 10 patients returned for 16 transfers 6 pregnancies, 4 using a gestational carrier 4 singletons, 1 twin, 1 ectopic Gestational ages at delivery 36 39 weeks 50% of patients returning had delivery from their embryos One patient spontaneously conceived after failed Ets 2 patients had failed ETs, then delivered with donor eggs Robertson AD, et al. Embryo Yield after In Vitro Fertilization in Women Undergoing Embryo Banking for Fertility Preservation Before Chemotherapy. Fertil Steril 2011
Pregnancy in Cancer Survivors Delivery rates in older patients unclear Likely c/w pregnancy rates with embryo cryopreservation No evidence of increased risk of birth defects or chromosome abnormalities in babies born from a parent with current cancer or history of cancer Some chemotherapeutic agents are teratogenic Insufficient numbers of live births after fertility preservation published to confirm this. Azim AA, et al. Safety of Fertility Preservation by Ovarian Stimulation with Letrozole and Gonadotropins in Patients with Breast Cander: a Prospective controlled Study. J Clin Oncol, 2008
Ovarian Suppression
Meta-analysis of Menses with Ovarian Suppression Shen YW et al. Utility of Gonadotropin Releasing Hormone Agonists for Prevention of Chemotherapy Induced Ovarian Damage in premenopausal Women with Breast Cancer: A Systematic Review and Meta Analysis. Onco Targes Ther. 2015.
Meta-analysis of Pregnancy with Ovarian Suppression Shen YW et al. Utility of Gonadotropin Releasing Hormone Agonists for Prevention of Chemotherapy Induced Ovarian Damage in premenopausal Women with Breast Cancer: A Systematic Review and Meta Analysis. Onco Targes Ther. 2015.
Goserelin For Ovarian Suppression 257 randomized 218 evaluable 135 with complete data Ovarian failure: 8% Goserelin 22% chemo alone OR 0.30(0.09,0.97) Pregnancy: 21% Goserelin 11% chemo (P=0.03) Delivery rates similar Halle CF, et al. Goserelin for Ovarian Protection during Breast Cancer Adjuvant Chemotherapy. N Engl J Med, 2015.
Ovarian Tissue Banking Laparoscopic oophorectomy or ovarian biopsies No ovarian stimulation, minimal delay in treatment (only option in prepubertal girls) Autologous transplantation human births All births after orthotopic transplant Risk of seeding cancer cells in cancer that involve the ovaries Repeat surgery required Grafts function hormonally for 3 8 years but AMH levels are low In vitro maturation of eggs from tissue no deliveries yet
Ovarian Cortical Tissue 20 yo, acute leukemia; urgent TBI, chemo, stem cell transplant 11 yo acute leukemia; TBI, chemo, stem cell transplant 18 mo, pelvic sarcoma; pelvic radiation and chemotherapy
Serum AMH Decrease Prevented by Everolimus Goldman KN, et al. mtorc1/2 Inhibition Preserves Ovarian Function and Fertility During Genotoxic Chemotherapy. PNAS 2017
Conclusions All breast cancer patients should be informed of the potential impact on fertility of chemotherapy and delay to conception Fertility preserving options should be discussed Technologies pose some risk Delay cancer therapy, costly Ovarian tissue cryo still experimental Live birth rates with banked eggs and embryos are still unclear We should target those at highest risk of infertility But we can t predict this with accuracy Available options must be weighed against time, risk of infertility and cost
Everolimus and Ovarian Protection Goldman KN, et al. mtorc1/2 Inhibition Preserves Ovarian Function and Fertility During Genotoxic Chemotherapy. PNAS 2017
Letrozole Simulation: Data Cases Letrozole Control P value Age 36.4 + 3.6 36.9 + 3.9 0.44 Baseline FSH 7.1 + 3.1 4.2 + 2.0 <0.001 Peak estradiol 483.4 + 278.9 1464 + 644.9 <0.001 Days of 11.7 + 2.3 12.2 + 1.5 0.09 stimulation Oocytes retrieved 12.4 + 7.0 11.1 + 5.5 0.43 # 2PN zygotes 6.6 + 4.0 6.9 + 4.1 0.73 Compared 47 breast cancer patients (86% ER positive) undergoing letrozole stimulation to 56 age matched controls undergoing IVF with downregulation protocol Breast cancer patients had higher baseline FSH but similar response to stimulation and lower peak estradiol levels Oktay K, et al. Letrozole Redues Estrogen and Gonadotropin Exposure in Women with Breast Cancer Undergoing Ovarian Stimulation before Chemotherapy. J Clin Endocrinol Metab, 2006.
RCTs of Ovarian Suppression Through Treatment Investigator Bawady Sverrisdottir Del Mastro Leonard Gerber Munster Elgindy SWOG 0230 Year 2009 2009 2011 2010 2011 2012 2013 2014 ASCO Patients (n) 80 285 281 227 60 49 100 257 Study type Phase II RCT Substudy from combined analysis of 4 RCTs using core protocol Treatment arms CT + goserelin vs CT TAM^ +/ CT TAM +/ CT Goserelin +/ CT Goserelin/TAM +/ CT Phase III RCT Phase III RCT (abstract only) Phase II RCT Phase III RCT Phase II RCT Phase III RCT CT + triptorelin vs. CT CT + goserelin vs. CT CT + goserelin vs. CT CT + triptorelin vs. CT Delayed CT : CT + triptorelin vs. CT Early CT : CT + triptorelin + cetrorelixβ vs. CT CT + goserelin vs. CT Median age [range] 30 [26 33] 45 [29 55] 39 [24 45] NR 37 [26 47] 39 [21 43] 33 [18 40] 38 [25 49] Premenopausal Regular menstruation Actively menstruation definition FSH <10 IU/L during 6 weeks pre CT LMP <6 months prior to study entry, including irregular cycles Regular menses in 12 months preceding surgery Regular menstruation FSH<15 in follicular phase Regular menstruation ( 3 periods in 6 months, lasting 2 days, 21 35 days apart FSH <40 IU/L Regular menstruation ( 3 consecutive periods within 21 35 days) %ER+ NR 45% 81% NR 0% 73% 0% 0% Marker of fertility Resumption of Resumption of Resumption of Resumption of Resumption of Resumption of preservation menstruation menstruation menstruation menstruation menstruation menstruation Primary endpoint Resumption of menstruation or spontaneous ovulation Rate of POF (no Recovery of menstruation/ menstruation spontaneous ovulation) 3 months post CT Rate of CIA (no menstruation and postmenopausal FSH/E2 levels) for 12 months post CT Rate of amenorrhea 12 months after start of CT Rate of normal ovarian function at 6 months post CT Median f/u [range] NR [3 8 months] NR 12 months post CT NR 6, 12, 24, 48 months post CT Rate of recovery of menstruation: 90% (goserelin) vs. 33% (control), p<0.001 At 6 months post ET 91.1% (triptorelin) vs. cessation : 36% 74.1% (control) p<0.001 (goserelin) vs. 10% (control), 13% (TAM), 7% goserelin + TAM), p= 0.006 Pregnancies No data on pregnancies No data on pregnancies 3 pregnancies in triptorelin arm, 1 in control arm NR No statistically significant difference between treatment arms (further details not published) No data on pregnancies Uninterrupted or restored menstruation during f/u of at least 2 years post CT 18 months [5 43 months] after CT 70% (goserelin) vs. 56.7% 88.5% (triptorelin) vs. (control) 90.5% (control) Trial stopped early for futility 1 pregnancy in each group 2 pregnancies in control arm Rate of regular menstruation at 12 months after completion of CT LMP < 6 weeks prerandomisation or FSH & E2 in premenopausal range Resumption of menstruation, postmenopausal FSH, pregnancy Rate of ovarian failure (amenorrhea) at 2 years, FSH NR Planned f/u at 1,2 and 5 All patients followed for years at least 12 months At 12 months post CT 8% (goserelin) vs. 22% Delayed CT: (control) 72% (triptorelin) vs. 52% 18% vs. 9% pregnancy (control), p=0.15 success Early CT: Trial stopped prior to full 60% (triptorelin + accrual due to funding cetrorelix) vs 48% issues (control), p=0.39 3 pregnancies, one in Pending early CT + triptorelin + cetrorelix arm, 1 in early CT control arm and 1 in delayed CT + triptorelin arm Adapted from Turner NH, et al. Utility of Gonadotropin Releasing Hormone Agonists for Fertility Preservation in Young Breast Cancer Patients: the Benefit Remains Uncertain. Ann. Oncol., 2013